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Primary brain tumors, including germ cell tumors (GCTs), are a diverse group of diseases that together constitute the most common solid tumor of childhood. The most recent classification of CNS tumors implements molecular parameters for the first time, in addition to histology, to define brain tumor entities. This led to restructuring some CNS tumor types, such as embryonal tumors and gliomas; however, per this updated classification schema, no molecular parameters are used to classify intracranial GCTs. Tumor location and extent of disease (brain invasion and tumor spread) remain important factors that affect treatment and prognosis.
Primary CNS GCTs are a heterogeneous group of neoplasms that are more common in Japan and other Asian countries than in North America and Europe. In North America, they account for approximately 4% of all primary brain tumors, with a peak incidence from age 10 years to age 19 years and a male predominance in a pineal location.[1,2,3]
CNS GCTs are broadly classified as germinomatous and nongerminomatous germ cell tumors (NGGCTs) on the basis of clinicopathological and laboratory features, including tumor markers.[4,5] An alternative therapeutic classification in Japan distinguishes three groups on the basis of their prognostication: good prognosis (e.g., germinoma), intermediate prognosis (e.g., teratoma with malignant transformation), and poor prognosis (e.g., yolk sac tumor, choriocarcinoma, embryonal carcinoma, and mixed tumors of those entities).
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization Classification of Tumors of the Central Nervous System.[4,5] For a full description of the classification of CNS tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.
In Western countries, GCTs represent 3% to 4% of primary brain tumors in children; however, series from Japan and Asia report the incidence of CNS GCTs as approximately 15% of pediatric CNS tumors.[3,6,7,8] The genetic or environmental reasons for these differences remain unknown.
CNS GCTs usually arise in the pineal and/or suprasellar regions of the brain, as solitary or multiple lesions (refer to Figure 1). The most common site of origin is the pineal region (45%), and the second most common site is the suprasellar region (30%) within the infundibulum or pituitary stalk. Both of these sites are considered extra-axial or nonparenchymal CNS locations. Approximately 5% to 10% of patients present with synchronous tumors arising in both the suprasellar and pineal locations, and the histology is most frequently a germinoma. Males have a higher incidence of GCTs than do females, with males having a preponderance of pineal-region primary tumors. Other areas that may be involved, though rare, include the basal ganglia, ventricles, thalamus, cerebral hemispheres, and medulla.[9,10]
Figure 1. Anatomy of the inside of the brain. The supratentorium contains the cerebrum, ventricles (with cerebrospinal fluid shown in blue), choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The infratentorium contains the cerebellum and brain stem.
In a study of 62 cases of intracranial GCTs, next-generation sequencing, single-nucleotide polymorphism array, and expression array showed frequent mutations in the KIT/RAS signaling pathway (50% of cases) and the AKT/mTOR pathway (19% of cases).
To identify genes and specific pathways that may be involved in CNS tumorigenesis, tumors were profiled for DNA copy-number alterations and loss of heterozygosity using single-nucleotide polymorphism array and quantitative real-time polymerase chain reaction. These investigators found alterations of CCND2 (12p13) and RB1 (13q14), suggesting that this may implicate the cyclin/CDK-RB-E2F pathway in tumor formation. Gains in PRDM14 (8q13) were also noted.
The signs and symptoms of CNS GCTs depend on the location of the tumor in the brain, as follows:
Nonspecific symptoms such as enuresis, anorexia, and psychiatric complaints  can lead to delays in a diagnosis, whereas signs of increased intracranial pressure or visual changes tend to result in an earlier diagnosis.
Radiographic characteristics of CNS GCTs cannot reliably differentiate germinomas from NGGCTs or other CNS tumors. The diagnosis of GCTs is based on the following:
The diagnosis of a suspected CNS GCT and an assessment of the clinical deficits and extent of metastases can usually be confirmed with the following tests:
If possible, a baseline neuropsychologic examination should be performed after symptoms of endocrine deficiency and raised intracranial pressure are resolved.
A diagnosis of GCTs often requires a tumor biopsy, except when characteristic increased tumor markers are found in the serum and/or CSF. When the tumor markers are negative or mildly elevated but below diagnostic criteria, or if there is any noncharacteristic finding, a tumor biopsy is performed.
It is crucial that appropriate staging is determined and that pure germinomas are distinguished from NGGCTs. Chemotherapy and radiation treatment plans differ significantly depending on GCT category and extent of disease.
The pathogenesis of intracranial germ cell tumors (GCTs) is unknown. The germ cell theory proposes that central nervous system (CNS) GCTs arise from primordial germ cells that have aberrantly migrated and undergone malignant transformation. A genome-wide methylation profiling study of 61 GCTs supports this hypothesis. An alternative hypothesis, the embryonic cell theory, proposes that GCTs arise from a pluripotent embryonic cell that escapes normal developmental signals and progresses to CNS GCTs.[2,3]
Previous molecular studies comparing the genomic alterations in GCTs showed similar copy-number alterations whether the GCT was systemic or CNS based.
The World Health Organization has classified CNS GCTs into the following groups:
In addition to the microscopic appearance of the various CNS GCTs, tumor markers (proteins, such as alpha-fetoprotein [AFP] and beta subunit human chorionic gonadotropin [beta-HCG], secreted by the tumor cells) found in the serum and cerebrospinal fluid (CSF) aid in diagnosis (refer to Tables 1 and 2).
The diagnosis and classification of CNS GCTs can be made on the basis of histology alone, tumor markers alone, or a combination of both.[5,6,7] There is an effort to use tumor markers for prognostication on the basis of the presence and degree of elevation of AFP and beta-HCG. This is an evolving process, and cooperative groups in North America, Europe, and Japan have adopted slightly different criteria. For example, groups in the United States and Europe consider tumors to be secreting or mixed GCTs if serum and/or CSF AFP levels are 10 ng/mL or higher and/or serum and/or CSF beta-HCG levels are 50 IU/L or higher; however, several European and Asian groups designate tumors with serum and/or CSF AFP levels of 50 ng/mL or higher and/or beta-HCG levels of 100 IU/L or higher as secreting GCTs. Patients with pure germinomas and teratomas usually present with negative markers, but low levels of beta-HCG can be detected in patients with germinomas.
Favorable-risk germinomas can secrete low levels of beta-HCG resulting from a syncytiotrophoblastic component. Nongerminomatous germ cell tumors (NGGCTs) can consist of one malignant NGGCT type (e.g., embryonal carcinoma, yolk sac tumor, endodermal sinus tumor, or choriocarcinoma) or contain multiple elements of GCT components, including teratomatous or germinomatous constituents.
Elevations of tumor markers along with imaging findings are used as surrogate diagnostic markers for CNS GCT and may obviate the need for a histologic diagnosis. The tumor markers AFP and beta-HCG are the most useful, although other markers, such as placental alkaline phosphatase and c-kit, are being investigated. Distinguishing between different GCT types by CSF protein marker levels alone is somewhat arbitrary, and standards vary across continents. Patients with pure germinomas and teratomas usually present with negative markers, but very low levels of beta-HCG can be detected in patients with germinomas. Current efforts are directed at determining a marker threshold for beta-HCG–secreting germinomas, because data suggest that the beta-HCG levels of 50 mIU/mL in Europe and 100 mIU/mL in North America that are used to distinguish germinomas from NGGCTs are questionable.
The use of tumor markers and histology in GCT clinical trials is evolving. For example, in the COG-ACNS1123 (NCT01602666) trial, patients are eligible for assignment to the germinoma regimen without biopsy confirmation if they have one of the following:
Alternative classification schemes for CNS GCTs have been proposed by groups such as the Japanese Pediatric Brain Tumor Study Group for CNS GCTs, who based their stratification on the prognostic grouping of the differing histologic variants, as shown in Table 3. Pure germinomas and mature teratomas fall into the good prognostic group; choriocarcinomas, yolk sac tumors, embryonal carcinomas, or mixtures of these three histologic subtypes fall into the poor prognostic group.
There is no universally accepted clinical staging system for germ cell tumors (GCTs), but a modified Chang staging system has been traditionally used. Staging evaluation of central nervous system GCTs includes the following:
Serum tumor markers are often obtained for AFP and beta-HCG; however, they do not serve as a substitute for CSF tumor markers, if lumbar CSF can be safely obtained.
Patients with localized disease and negative CSF cytology are considered to be M0 (metastatic negative); patients with positive CSF cytology or patients with drop metastasis (spinal or cranial subarachnoid metastases that arise from intracranial lesions) are considered to be M+ (metastatic positive). Appropriate staging is crucial because patients with metastatic disease may receive higher total doses of radiation and more extended radiation fields.
GCTs may be disseminated throughout the neuraxis at the time of diagnosis or at any disease stage. Several patterns of spread may occur in germinomas, such as subependymal dissemination in the lateral or third ventricles and parenchymal infiltration. Rarely, extracranial spread to lung and bone has also been reported.[3,4]
Patients with bifocal intracranial germinomas limited to the suprasellar and pineal region are being treated in the same manner as are patients with synchronous, localized, nonmetastatic tumors in ongoing studies in North America (COG ACNS1123 [NCT01602666]) and Europe (SIOP CNS GCT II [NCT01424839]).
Teratomas, germinomas, and other nongerminomatous germ cell tumors (NGGCTs) have differing prognoses and require different treatment regimens. Studies have observed the following:[1,2,3,4,5]
Table 4 outlines the treatment options for newly diagnosed and recurrent childhood CNS GCTs.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Treatment Options for Newly Diagnosed Childhood CNS Germinomas
Treatment options for newly diagnosed childhood central nervous system (CNS) germinomas include the following:
Germinomas are highly radiosensitive and have been traditionally treated successfully with radiation therapy alone. Historically, patients with nondisseminated disease have been treated with craniospinal irradiation plus a boost to the region of the primary tumor. The dose of craniospinal irradiation has ranged from 24 Gy to 36 Gy, although studies have used lower doses. The local tumor dose of radiation therapy has ranged between 40 Gy and 50 Gy. Studies of lower-dose craniospinal irradiation have shown excellent outcomes. This modification has resulted in 5-year overall survival rates of higher than 90%.; [Level of evidence: 2A]; [4,5][Level of evidence: 3iA] These excellent survival rates have allowed investigators to focus on reducing radiation treatment volume and dose in an attempt to decrease late effects.[3,6,7]
Patterns of relapse after craniospinal irradiation versus reduced-volume radiation therapy (whole-brain or whole-ventricular radiation therapy) have supported the omission of craniospinal irradiation for localized germinomas.[8,9,10] On the basis of these results, the treatment for patients with localized germinomas has been modified to cover the whole ventricular system (24 Gy) followed by a boost to the primary site (40–45 Gy), rather than to deliver radiation therapy to the entire craniospinal axis or even to the whole brain. This change has not resulted in worse outcomes and is expected to minimize the acute and long-term toxicity of radiation therapy. Focal radiation therapy directed only to the tumor volume, even after neoadjuvant chemotherapy, results in inferior outcomes compared with whole-brain or whole-ventricle radiation therapy; therefore, focal radiation therapy is not recommended.
Neoadjuvant chemotherapy followed by response-based radiation therapy
Chemotherapy has been explored in an effort to reduce radiation therapy doses and associated neurodevelopmental morbidity. Several studies have confirmed the feasibility of this approach for maintaining excellent survival rates, but the number of treated patients is small.[11,12,13][Level of evidence: 2A]; [14,15][Level of evidence: 3iA]; [Level of evidence: 3iiiC]
Chemotherapy agents such as cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin are highly active in CNS germinomas. Patients receiving chemotherapy agents that require hyperhydration (e.g., cyclophosphamide, ifosfamide, and cisplatin) are often quite challenging to manage because of the possibility of diabetes insipidus in patients with primary tumors of the suprasellar region.
An international group of investigators has explored a chemotherapy-only approach primarily for younger children. The investigators were able to achieve a complete response in 84% of patients with germinomas treated with chemotherapy alone. Fifty percent of these patients suffered tumor relapse or progression; many recurrences were local, local plus ventricular, and ventricular alone and/or with leptomeningeal dissemination throughout the CNS, which required additional therapy, including radiation. Subsequent studies have continued to support the need for radiation therapy after chemotherapy and the likely requirement for whole-ventricular irradiation (24 Gy) with local tumor site–boost (total dose, 40 Gy).[Level of evidence: 2A]; [Level of evidence: 3iiiA] Excellent results have also been reported for patients with metastatic germinomas who received craniospinal irradiation of 24 Gy with local tumor site–boost (total dose, 40 Gy).[Level of evidence: 2A]
Optimal management of bifocal lesions is less clear, but most investigators consider this presentation a form of multifocal primary disease to be staged as M0. A meta-analysis of 60 patients demonstrated excellent progression-free survival after craniospinal irradiation alone. Chemotherapy plus localized radiation therapy, including whole-ventricular irradiation, also resulted in excellent disease control.[Level of evidence: 3iiDiii]
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood CNS Germinomas
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Treatment Options for Newly Diagnosed Childhood CNS Teratomas
Teratomas are designated as mature or immature on the basis of the absence or presence of differentiated tissues. The Japanese Pediatric Brain Tumor Study Group stratifies teratomas for classification and intensity of treatment (chemotherapy and radiation) into the good-risk group (mature teratomas) and intermediate-risk group (immature teratomas) (refer to Table 3), while the Children's Oncology Group includes immature teratomas with other nongerminomatous germ cell tumors.
Treatment options for newly diagnosed childhood central nervous system teratomas include the following:
The primary treatment for teratomas is maximal surgical resection. Adjuvant treatment in the form of focal radiation therapy and/or adjuvant chemotherapy for subtotally resected tumors is controversial, with small institutional series suggesting potential utility for the use of stereotactic radiosurgery.[1,2][Level of evidence: 3iA]
The prognosis for children with central nervous system (CNS) nongerminomatous germ cell tumors (NGGCTs) remains inferior to that for children with germinomas, but the difference is diminishing with the addition of multimodality therapy. With the current treatment regimens, the 10-year overall survival (OS) for NGGCTs ranges between 70% and 80%.[1,2] NGGCTs are radiosensitive, but survival after standard craniospinal irradiation alone has been poor, ranging from 20% to 45% at 5 years. In patients with NGGCTs who suffer tumor relapse, most relapses occur within 18 months.
Treatment Options for Newly Diagnosed Childhood CNS NGGCTs
Treatment options for newly diagnosed childhood CNS NGGCTs include the following:
The optimal treatment regimen for CNS NGGCTs remains unclear.
Chemotherapy followed by radiation therapy
Anticancer agents that have been used include carboplatin, etoposide, bleomycin, ifosfamide, and vinblastine in different combinations. The use of chemotherapy before radiation therapy has increased survival rates, but the specific chemotherapy regimen and length of therapy and the optimal radiation field, timing, and dose remain under investigation.[1,3,4] Some investigators have proposed radiation therapy fields that are smaller than those used for craniospinal irradiation (e.g., whole-ventricular irradiation with a boost to the local tumor site) for patients with nondisseminated NGGCT. Controversy exists over the pattern of tumor relapse in patients treated with chemotherapy and focal radiation.[1,2,5,6]
Evidence (chemotherapy followed by radiation therapy):
A small percentage of patients treated with chemotherapy may have normalization of tumor markers with a less-than-complete radiographic response. Occasionally, a mass continues to expand in size even though tumor markers may have normalized. This condition is frequently designated as growing teratoma syndrome and may represent a lack of response by the more mature germ cell components (such as immature teratoma) to chemotherapy with or without radiation therapy.[7,9,10] In such circumstances, surgery is usually required for debulking, histologic confirmation, and exclusion of mixed germ cell tumor components.
A second-look surgery can help determine whether the residual mass contains teratoma, fibrosis, or residual NGGCT.[2,11] If second-look surgery finds mature teratoma or fibrosis after chemotherapy, the general approach is to proceed with radiation therapy as if the patient had achieved a CR to chemotherapy. However, if an active tumor is observed, then alternative treatment approaches are generally considered.
Treatment Options Under Clinical Evaluation for Newly Diagnosed Childhood CNS NGGCTs
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The most common type of relapse for childhood central nervous system (CNS) germ cell tumors (GCTs) is local recurrence at the primary tumor site; however, 30% of relapses are outside the primary site and/or combined with leptomeningeal spread. The outcome for patients with relapse, especially those with nongerminomatous germ cell tumors (NGGCTs), remains poor.
Treatment Options for Recurrent Childhood CNS GCTs
Treatment options for recurrent childhood CNS GCTs include the following:
Patients with germinomas that were treated initially with chemotherapy only can benefit from chemotherapy followed by radiation therapy.[1,2] Reirradiation after chemotherapy at recurrence has been utilized.[2,3,4]
For pure germinoma patients who previously received radiation therapy, myeloablative chemotherapy with stem cell rescue has been used.[5,6] High-dose chemotherapy and autologous stem cell rescue may also have curative potential for a minority of patients with relapsed systemic NGGCTs.[4,5,6,7,8]
Enrollment on clinical trials should be considered for all patients with recurrent disease. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.
Treatment Options Under Clinical Evaluation for Recurrent Childhood CNS GCTs
Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
A significant proportion of children with central nervous system (CNS) germ cell tumors (GCTs) present with endocrinopathies, including diabetes insipidus and panhypopituitarism. In most cases, these endocrinopathies are permanent despite tumor control, and patients will need continuous hormone replacement therapy.[1,2]
Although significant improvements in the overall survival of patients with CNS GCTs have occurred, patients face significant late effects based on the location of the primary tumor and its treatment. Treatment-related late effects include the following:
Current clinical trials and therapeutic approaches are directed at minimizing the long-term sequelae that result from the treatment of CNS GCTs.
Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in survivors of childhood and adolescent cancer.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed and extensively revised.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system germ cell tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Central Nervous System Germ Cell Tumors Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Central Nervous System Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-cns-germ-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389498]
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Last Revised: 2018-01-24
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